Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br(O)(=O)=O.[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH2:13])=[NH:12])[CH2:7][CH2:6]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])=O.CC(C)([O-])C.[Na+]>C(O)(C)(C)C>[OH:23][CH2:24][CH2:25][C:21]1[C:22]([OH:26])=[N:12][C:11]([N:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[N:13][C:19]=1[C:18]1[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1cccc(C(=O)C2CCOC2=O)c1
Reactant: N=C(N)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: CC(C)(C)O
Product: COc1cccc(-c2nc(N3CCOCC3)nc(O)c2CCO)c1

Procedure:
Morpholinoformamidine bromate salt (200 mg, 0.952 mmol), 3-(3-methoxybenzoyl)-dihydrofuran-2-one (419 mg, 1.904 mmol) and sodium t-butoxide (183 mg, 1.904 mmol) were added into a microwave reaction tube, followed by being dissolved in t-butanol (3 ml). After irradiation of microwave (200 W, 120° C.) for 1 hour, the solvent was removed under reduced pressure, to obtain a crude product as a brown solid. The crude was purified by silica gel column chromatography (DCM/MeOH=95/5), to obtain 5-(2-hydroxyethyl)-6-(3-methoxyphenyl)-2-(morpholin-4-yl)-pyrimidin-4-ol, and 4-(3-methoxyphenyl)-2-(morpholin-4-yl)-5,6-furo[2,3-d]pyrimidine as colorless solid.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([O:19]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: CCOC(=O)c1[se]c(C(C)(C)C)cc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc(C(C)(C)C)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (200 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carboxylate (1.2 g) in THF (30 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as a pale brown color solid, which was recrystallized from chloroform-hexane (300 mg, 28%), mp 218-220° C. IR (Neat) νmax 3337, 3156, 2958, 1631, 1602, 1326, 1250, 1219, 1177, 1113, 1006 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.20 (1H, s, —CONH2), 7.41 (1H, s, H-4), 6.01 (1H, br s, —CONH2), 3.56 (3H, s, —NCH3), 3.16 (3H, s, —NCH3), 1.37 (9H, s, t-butyl); 13C NMR (100 MHz, DMSO-d6): δ 168.0, 166.1, 151.1, 129.0, 116.9, 36.8, 32.4; LC-MS (positive ion mode): m/z 323, 325 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:37][CH2:38][CH3:39])[C:35]=1[F:36])[CH:31]=O)[CH3:26].C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[C:34]([O:37][CH2:38][CH3:39])[C:35]([F:36])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(F)c(OCC)c3)CC2)c1
Temperature: 50 °C
Yield: 94.2 %

Procedure:
0.33 g (1.0 mmol) of 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester and 0.23 g (1.10 eq.) of 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), were dissolved under argon in 6 mL of MeOH; 0.39 mL (0.29 g=2.25 eq.) of N-ethyl-diisopropylamine and 0.11 mL (0.12 g=2.0 eq.) of glacial acetic acid were added and the mixture then heated for 2 h at 50° C. After cooling down to rt, 0.16 g (2.5 eq.) of sodium cyanoborohydride was added and the reaction mixture heated again for 1.5 h at 50° C. It was then poured into crashed ice, the pH was adjusted to ˜10 with sodium carbonate solution and the mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 0.50 g of the title compound as colorless oil. MS: 531.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:11]([F:14])([F:13])[F:12])[C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:26]([O:21][CH2:18][C:19]#[CH:20])[C:25]#[CH:24].[F:1][C:2]([F:22])([F:23])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:11]([F:13])([F:14])[F:12])[C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOCC#C

Procedure:
A solution of 168.12 g. (0.5 mole) of hexafluorobisphenol A in 1000 ml of acetone was reacted with 142.76 g. (1.2 moles) of propargyl bromide in the presence of 165.85 g. (1.2 moles) of potassium carbonate. The reaction mixture was stirred and heated under reflux for 72 hrs. After cooling it was filtered and the solvent (acetone) of the filtrate was evaporated on a Buchi Re 121 Rotavapor. The residue was dissolved in diethyl ether and washed first with a 5% NaOH solution and then three times with deionized water. Dipropargyl ether of hexafluorobisphenol A was obtained in 90% yield after evaporation of diethyl ether on a Rotavapor. The product was a light brown liquid with the following structure. ##STR11##
Reaction SMILES: Cl[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[CH:14]=[CH:13][C:6]([CH2:7][N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCc1ccc(Cn2cccc2)cc1
Reactant: C1CCNC1
Product: c1ccn(Cc2ccc(CN3CCCC3)cc2)c1

Procedure:
The title compound was prepared starting from 1-(4-chloromethyl-benzyl)-pyrrole (preparation in example 20 step A) and pyrrolidine by the same method reported in Example 19 step B. 1H NMR (400 MHz, MeOD-d4)δ7.26 (m, 2 H), 7.15 (m, 2 H), 7.05 (m, 2 H), 6.85 (m, 2 H), 6.57 (t, J=2.1 Hz, 2 H), 5.96 (t, J=2.1 Hz, 2 H), 4.98 (s, 2 H), 4.92 (s, 2 H), 3.50 (s, 3 H), 2.50 (m, 2 H), 1.70 (m, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N:12]=[CH:13][N:14](C)C.Cl.[CH:18]([O:21]N)([CH3:20])[CH3:19].C(N(CC)CC)C.C1(C)C=CC=CC=1>C(O)C>[CH:18]([O:21][N:14]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1)([CH3:20])[CH3:19]
Reactant: CN(C)C=Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)On1cnc2cnc3ccccc3c21
Reaction time: 5 h
Yield: 78.1 %

Procedure:
A solution of N′-(4-chloroquinolin-3-yl)-N,N-dimethylimidoformamide (9.3 g, 0.040 mol) and O-isopropylhydroxylamine hydrochloride (5.0 g, 45 mmol) in ethanol (150 mL) was heated at reflux overnight. An analysis by LC/MS indicated the reaction was incomplete, and triethylamine (2.0 mL) was added. The reaction was heated at reflux for three hours and found to be incomplete. The ethanol was removed under reduced pressure, and toluene (150 mL) was added. The reaction was heated at reflux overnight but was found again to be incomplete. The toluene was removed under reduced pressure, and ethanol (150 mL) and additional O-isopropylhydroxylamine hydrochloride (1.0 g, 9.0 mmol) were added. The reaction was heated at reflux over night with additional O-isopropylhydroxylamine hydrochloride (0.5 g) added after three hours and again (0.4 g) after five hours. The work-up and purification procedures described in Part C of Example 19 were followed with the modification that chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent. 1-Isopropoxy-1H-imidazo[4,5-c]quinoline (7.1 g) was obtained as a light red solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1>C1COCC1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Nc1ccc(Oc2nccnc2C2=CCCOC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Palladium (10 mg, 0.0094 mmol, 10% wt. on activated carbon) was added to a stirred solution of 4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.16 g, 0.59 mmol) in THF (3 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 23 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 272.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[C:4]([CH2:11]Br)[CH:3]=1.C1C[O:16]CC1.[OH-].[Li+].Cl>O.CO>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH2:11][OH:16])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1CBr
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(Br)cc1CO
Temperature: 90 °C

Procedure:
In a 15 mL microwave reaction vial, was added methyl 5-bromo-3-(bromomethyl)thiophene-2-carboxylate (700 mg, 2.23 mmol), THF (4 mL) and MeOH (1 mL). To above solution was added lithium hydroxide (53.4 mg, 2.23 mmol, 1.0 eq) in water (1 mL). The reaction was heated in microwave reactor for 30 min at 90° C. The reaction was cooled down to r.t., neutralized with 1N HCl, extracted with EtOAc, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[O-:15][C:16]#[N:17].[K+]>O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[NH:17][C:16](=[O:15])[NH:1][CH:2]=1)([O-:13])=[O:12]
Reactant: N#C[O-]
Reactant: NCC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(Cc2ccccc2[N+](=O)[O-])[nH]1
Temperature: 60 °C
Yield: 52.6 %

Procedure:
A solution of 1-amino-3-(2-nitrophenyl)-propan-2-one 3a (138 mg, 0.6; Alazard et al. Tetrahedron 1994, 50, 6287–6298) in water was reacted potassium cyanate (97 mg, 1.2 mmol) and heated in a 60° C. oil bath for 4 h. The reaction was purified by reverse-phase HPLC to give 82 mg (62% yield) of 4-(2-nitrobenzyl)-1,3-dihydroimidazol-2-one 3b. MS found: (M+MeCN)+=261.
Reaction SMILES: [ClH:1].C(OC(OCC)[CH2:6][CH2:7][CH2:8][NH2:9])C.[C:13]1([CH:23]([CH2:26][OH:27])[CH2:24][OH:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[CH:28]1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:1].[NH2:9][CH:8]([CH3:28])[CH2:7][CH:6]1[O:25][CH2:24][CH:23]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:26][O:27]1
Reactant: c1ccccc1
Reactant: OCC(CO)c1cccc2ccccc12
Reactant: CCOC(CCCN)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CC(N)CC1OCC(c2cccc3ccccc23)CO1
Reaction time: 4 h

Procedure:
Sufficient ethereal hydrogen chloride is added to 4 g (25 mmol) of 4,4-diethoxybutylamine in 500 ml of benzene to precipitate all the hydrochloride. 4 g (20 mmol) of 2-(naphthalen-1-yl)propane-1,3-diol in 200 ml of benzene and 100 mg of paratoluenesulphonic acid are then added, and the mixture is evaporated to dryness in a bath at 100° C. A further 700 ml of benzene are added, the mixture is evaporated under the same conditions, and the residue is then placed in vacuo at 100 C for 4 h. It is recrystallised in diethyl ether, dried at 60° C., recrystallised twice in ethanol, treating it with vegetable charcoal during the first recrystallisation, washed with diethyl ether and dried at 80° C. 3.2 g (10.4 mmol) of product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.[N+](=[CH2:23])=[N-]>C1COCC1>[CH3:23][O:18][C:17](=[O:19])[CH:16]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)[CH3:20]
Reactant: C=[N+]=[N-]
Reactant: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: C1CCOC1
Product: COC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 0.33 h

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid is dissolved in 10 ml. of THF and an ethereal solution of diazomethane is added dropwise, with stirring, until no further evolution of nitrogen is observed. After 20 minutes, the mixture is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid methyl ester, m.p. 90°-92°.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C#C>N1C=CC=CC=1>[C:10]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C#CCC(O)CCCC
Agent: C#C
Solvent: c1ccncc1
Solvent: O
Product: C#CCC(CCCC)OC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λmax. 3240 (terminal acetylene) and 1730 cm-1 (benzyloxy group).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:30][CH3:31])[CH2:28]C)[CH3:26].[Cl:32]C(Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:28](=[O:35])[N:27]([CH2:30][CH3:31])[CH2:25][CH3:26])[CH2:21][CH2:22]2)[C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)N1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: Cl
Reaction time: 16 h

Procedure:
A solution of 5 g (0.015 mol) of 1-[2-[(4,4'-Difluorobenzhydryl)oxy]ethyl]piperazine. 50 ml toluene and 3 ml (0.02 mol) triethylamine was added dropwise to a solution of 1.5 g (0.005 mol) triphosgene in 100 ml toluene at 5°-10° C. for 1 h. The mixture was allowed to stand at room temperature for 16 h and then washed with 1-N NaOH and water, dried over sodium sulphate. Evaporation of the solvent yielded the crude base as an oil.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:12]([O:14][C:15]([C:17]1[C:18]([Cl:23])=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16])[CH3:13]>O1CCOCC1>[ClH:23].[ClH:23].[CH2:12]([O:14][C:15]([C:17]1[C:18]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]2)=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cncnc1Cl
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)c1cncnc1N1CCN(CC(O)CO)CC1
Product: Cl

Procedure:
Grams 7.4 of 1-(2,3-dihydroxypropyl)piperazine and 4.3 g of 4-chloropyrimidine-5-carboxylic acid ethyl ester were warmed to 90° C. for 45 minutes in 100 ml dioxane. The reaction mixture was then settled, the supernatant liquor evaporated to dryness and the residue dissolved in hydrochloric ethanol and diluted with isopropanol until complete precipitation. By addition of 95° ethanol, the so formed gum crystallized and 4 g of 4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidine-5-carboxylic acid ethyl ester dihydrochloride, melting at 190°-193° C. (with decomposition), were obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9](S(=O)(=O)N)[C:10]=1NC1C=CC=CC=1)[C:5](O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([S:39](=[O:48])(=[O:47])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:31]=1[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27].[CH2:49](Br)[C:50]1C=CC=CC=1>>[CH2:49]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[C:30]([S:39](=[O:48])(=[O:47])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:31]([NH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:23]([NH:22][CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=2)[CH:24]=1)[CH3:50]
Reactant: Nc1cc(C(=O)O)cc(S(=O)(=O)Nc2ccccc2)c1Nc1ccccc1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
By replacing, in Example 52 A, 3-amino-4-anilino-5-sulphamyl-benzoic acid (2 g) by 3-amino-4-anilino-5-phenylsulphamyl-benzoic acid (4.4 g) and increasing the amount of benzyl bromide to 3.9 g, ethyl-4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate was obtained with a melting point of 166°-167° C.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].S(=O)(O)[O-].[Na+].[C-:26]#[N:27].[Na+].S(=O)(O)[O-]>O.C(Cl)(Cl)Cl.C(OCC)C>[OH:20][CH:19]([C:18]1[C:6]2[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]=2[CH:15]=[CH:16][CH:17]=1)[C:26]#[N:27]
Reactant: O=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: N#CC(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2.7 g. (0.010 mole) of 2-nitro-3-phenylbenzofuran-7-aldehyde (described in Belgian Patent 846,502, Example 13) and 20 ml. of diethyl ether is treated with 1.6 g. (0.015 mole) of sodium bisulfite in 10 ml. of water. After 30 minutes, 30 ml. of chloroform is added, followed by 1.5 g. (0.030 mole) of sodium cyanide in 5 ml. of water after an additional 30 minutes. About 0.7 g. of sodium bisulfite is added 1.5 hours later, and the mixture is cooled to 0° C. 30 minutes after the bisulfite addition and maintained for about 16 hours. The organic layer is separated, washed with aqueous sodium bisulfite solution, then with water, and dried over magnesium sulfate. Evaporation of the solution provides a solid which is recrystallized from a chloroform-heptane mixture to provide yellow crystals of α-hydroxy-2-nitro-3-phenylbenzofuran-7-acetonitrile, m.p. 137°-139° C.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH2:29][C:30]([NH2:32])=[O:31])=[CH:25][NH:26]2)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:32][C:30](=[O:31])[C:29]=2[C:24]2[C:23]3[C:27](=[CH:28][C:20]([C:19]([F:18])([F:33])[F:34])=[CH:21][CH:22]=3)[NH:26][CH:25]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C2=C(c3c[nH]c4cc(C(F)(F)F)ccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.40 g, 1.73 mmol) and 2-(6-trifluoromethyl-1H-indol-3-yl-acetamide (0.38 g, 1.57 mmol) in DMF (10 mL) was added absolution of potassium tert-butoxide in THF (1.0 M, 6.3 mL, 6.3 mmol) at room temperature. The reaction mixture was heated at 55° C. for 19 h, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1,5-dimethyl-1H-indol-7-yl)-4-(6-trifluoromethyl-1H-indol-3-yl)-pyrrole-2,5-dione (400 mg, 60.2%). 1HNMR (d6-DMSO, 400 MHz) 2.26 (s, 3H), 3.58 (s, 3H), 6.36 (d, J=3.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.76 (d, J=1.2 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 7.40 (s, 1H), 7.68 (s, 1H), 7.96 (d, J=2.8 Hz, 1H), 11.21 (s, 1H), 12.13 (s, 1H); MS (ES, m/z): C23H16F3N3O2: 424.13 (M++1): 422.23 (M+−1).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[C:5]1([C@H:2]2[NH:1][C:20](=[O:21])[CH2:19][O:4][CH2:3]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.3 %

Procedure:
To a mixture of (2R)-2-amino-2-phenyl-ethanol (10 g, 72.90 mmol) and triethylamine (18.45 g, 25.41 mL, 182.3 mmol) in THF (207.5 mL) at 0° C., was added 2-chloroacetyl chloride (8.234 g, 5.799 mL, 72.90 mmol) over 5 mins. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer separated, washed successively with water (2×100 mL), brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was then dissolved in THF (145.2 mL) and NaH (60% in mineral oil) (3.499 g, 87.48 mmol) was added portionwise over 5 mins at rt. On complete addition, the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and diluted with EtOAc (50 mL) and the organic layer separated, washed with sequentially with water (2×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by ISCO column companion system (330 g column, 0-10% MeOH/CH2Cl2). Product fractions were combined and concentrated in vacuo to leave the product as a pale yellow solid (5.2 g, 41% yield); 1H NMR (400.0 MHz, DMSO) d 3.55 (1H, m), 3.96 (1H, m), 4.08 (2H, s), 4.63 (1H, m), 7.29-7.40 (5H, m) and 8.46 (1H, s) ppm.